Research Papers:

A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers

Christopher J. Hanley, Fergus Noble, Matthew Ward, Marc Bullock, Cole Drifka, Massimiliano Mellone, Antigoni Manousopoulou, Harvey E. Johnston, Annette Hayden, Steve Thirdborough, Yuming Liu, David M. Smith, Toby Mellows, W. John Kao, Spiros D. Garbis, Alex Mirnezami, Tim J. Underwood, Kevin W. Eliceiri and Gareth J. Thomas _

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Oncotarget. 2016; 7:6159-6174. https://doi.org/10.18632/oncotarget.6740

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Christopher J. Hanley1, Fergus Noble1, Matthew Ward1, Marc Bullock1, Cole Drifka3, Massimiliano Mellone1, Antigoni Manousopoulou2, Harvey E. Johnston2, Annette Hayden1, Steve Thirdborough1, Yuming Liu3, David M. Smith1, Toby Mellows1, W. John Kao3, Spiros D. Garbis1,2, Alex Mirnezami1, Tim J. Underwood1, Kevin W. Eliceiri3,*, Gareth J. Thomas1,*

1Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK

2Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK

3Laboratory for Optical and Computational Instrumentation (LOCI), Department of Biomedical Engineering, University of Madison, Wisconsin 53706, USA

*These authors contributed equally to this work

Correspondence to:

Gareth J. Thomas, e-mail: [email protected]

Keywords: extracellular matrix, collagen, cancer associated fibroblasts, tumor microenvironment, second harmonic generation

Received: July 22, 2015     Accepted: December 05, 2015     Published: December 23, 2015


Collagen structure has been shown to influence tumor cell invasion, metastasis and clinical outcome in breast cancer. However, it remains unclear how it affects other solid cancers. Here we utilized multi-photon laser scanning microscopy and Second Harmonic Generation to identify alterations to collagen fiber structure within the tumor stroma of head & neck, esophageal and colorectal cancers. Image segmentation algorithms were then applied to quantitatively characterize these morphological changes, showing that elongated collagen fibers significantly correlated with poor clinical outcome (Log Rank p < 0.05). We used TGF-β treatment to model fibroblast conversion to smooth muscle actin SMA-positive cancer associated fibroblasts (CAFs) and found that these cells induce the formation of elongated collagen fibers in vivo. However, proteomic/transcriptomic analysis of SMA-positive CAFs cultured ex-vivo showed significant heterogeneity in the expression of genes with collagen fibril organizing gene ontology. Notably, stratifying patients according to stromal SMA-positivity and collagen fiber elongation was found to provide a highly significant correlation with poor survival in all 3 cancer types (Log Rank p ≤ 0.003). In summary, we show that increased collagen fiber length correlates with poor patient survival in multiple tumor types and that only a sub-set of SMA-positive CAFs can mediate the formation of this collagen structure.

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PII: 6740